Risk of nonovarian cancer in a nationwide-based study of nearly 5000 women with borderline ovarian tumors in Denmark.

Evidence regarding cancer risk after borderline ovarian tumors (BOTs) is limited. We conducted a nationwide cohort study examining the incidence of nonovarian cancers in women with serous or mucinous BOTs compared with the general female population with up to 41 years of follow-up. Through the nationwide Pathology Registry, we identified nearly 5000 women with BOTs (2506 serous and 2493 mucinous) in Denmark, 1978 to 2018. We computed standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) as relative risk estimates of specific nonovarian cancers. Compared with general female population rates, women with serous BOTs had increased rates of particularly malignant melanoma (SIR = 1.9; 95% CI: 1.3-2.6), thyroid cancer (SIR = 3.0; 95% CI: 1.4-5.4) and myeloid leukemia (SIR = 3.2; 95% CI: 1.5-5.8), and women with mucinous BOTs had elevated rates of lung cancer (SIR = 1.7; 95% CI: 1.3-2.1), pancreatic cancer (SIR = 1.9; 95% CI: 1.2-2.9) and myeloid leukemia (SIR = 2.3; 95% CI: 0.9-4.7). We found no convincing association with neither breast nor colorectal cancer in women with BOTs. This is the first large nationwide study showing that women with specific types of BOTs have increased risks of several nonovarian cancers, likely due to some shared risk factors or genetic characteristics.

Risk of specific types of ovarian cancer after borderline ovarian tumors in Denmark: A nationwide study.

Population-based evidence regarding risk of ovarian cancer after a borderline ovarian tumor (BOT) is sparse. We aimed to examine the incidence of specific types of ovarian cancer in women with serous or mucinous BOTs in a nationwide cohort study with up to 36 years of follow-up. Using the nationwide Danish Pathology Data Bank, we identified 4,281 women with a BOT (2,058 serous BOTs and 2,223 mucinous BOTs) in Denmark during 1978-2012. We computed standardized incidence ratios (SIRs) to compare the incidence of ovarian cancer among women with BOTs compared to general population rates. We found that a serous BOT was especially and strongly associated with subsequent serous ovarian cancer (SIR = 9.2; 95% CI: 6.8-12.2), and that a mucinous BOT was strongly related to mucinous ovarian cancer (SIR = 18.6; 95% CI: 10.8-29.8). The SIRs remained elevated ≥10 years after a serous BOT and up to 5-9 years after a mucinous BOT. The increased incidence of serous ovarian cancer in women with a serous BOT was mostly pronounced in women <50 years at the serous BOT diagnosis. In conclusion, women with a serous BOT experience long-term increased incidence of serous ovarian cancer, and women with a mucinous BOT have long-term elevated incidence of mucinous ovarian cancer compared to the general population. This is the first population-based study to show compelling evidence of the histo-specific increased risk of ovarian cancer following specific types of BOTs. Thus, these results are supportive of the hypothesis that BOTs may be precursor lesions to carcinomas of the corresponding histologic type.

Intratumoral Heterogeneity Accounts for Apparent Progression of Noninvasive Serous Tumors to Invasive Low-grade Serous Carcinoma: A Study of 30 Low-grade Serous Tumors of the Ovary in 18 Patients With Peritoneal Carcinomatosis.

Noninvasive ovarian low-grade serous tumors [atypical proliferative serous tumor (APST)/serous borderline tumor] appear to progress to invasive low-grade serous carcinoma (LGSC) at a low but regular rate. The underlying biology of this phenomenon is unknown. We studied 18 patients with 30 ovarian tumors (12 bilateral), including APST, noninvasive LGSC and invasive LGSC, who also had low-grade serous carcinomatosis. Tumors were evaluated for microinvasion (usual eosinophilic cell type), microinvasive carcinoma (<5 mm invasion of micropapillary nests), and overt carcinoma (≥5 mm invasion of micropapillary nests). Tumors were evaluated based on the original numerical order of sections under the hypothetical scenarios in which sampling was stopped at 1 section/cm and 2 sections/cm. Sampling based on 1 section/cm of greatest tumor dimension identified invasion of any type in 21 tumors (70%). Among these 21 tumors, 10 had microinvasive carcinoma, and 11 overt carcinoma. Sampling based on 2 sections/cm identified microinvasive carcinoma in 9 tumors and overt carcinoma in 14 tumors. With increased sampling from 1 to 2 sections/cm, the diagnosis in 3 tumors would have changed from microinvasive carcinoma to overt carcinoma, and in an additional 2 tumors from APST to APST with microinvasive carcinoma. Sampling based on >2 sections/cm changed the diagnosis in 1 additional case of APST with microinvasive carcinoma to overt carcinoma. These findings support that undetected (unsampled) occult invasion in the primary ovarian tumors is a likely explanation for some cases of apparent progression of noninvasive low-grade serous ovarian tumors to invasive LGSC. To minimize undetected occult invasion, consideration of sampling noninvasive low-grade ovarian serous tumors with at least 2 sections/cm of maximum tumor diameter may be warranted. The eosinophilic cell type of microinvasion, or microinvasive carcinoma, regardless of size, should prompt further sampling to identify overt carcinoma. The eosinophilic type of microinvasion was never seen alone in this cohort and by itself may be biologically insignificant.

Two types of primary mucinous ovarian tumors can be distinguished based on their origin.

The origin of primary mucinous ovarian tumors is unknown. We explore the hypothesis that they originate from either Brenner tumors or teratomas and examine differences between the tumors that arise in these settings. A total of 104 Brenner tumor-associated mucinous tumors and 58 teratoma-associated mucinous tumors were analyzed. Immunohistochemistry for 21 antigens and fluorescence in situ hybridization for ERBB2 and MYC were performed. Genome-wide copy number analysis and mutation analysis for 56 cancer-related genes was carried out on a subset of mucinous ovarian tumors and their complementary Brenner tumor or teratoma. Patients with teratoma-associated mucinous tumors were significantly younger than patients with Brenner tumor-associated mucinous tumors (43 vs. 61 years). During progression from cystadenoma to atypical proliferative mucinous (borderline) tumor to carcinoma expression of typical gastrointestinal markers was increased in both Brenner tumor-associated and teratoma-associated mucinous tumors. Brenner tumor-associated mucinous tumors showed more frequently calcifications and Walthard cell nests, rarely expressed SATB2 and showed more often co-deletion of CDKN2A and MTAP. Teratoma-associated mucinous tumors were characterized by mucinous stromal dissection, SATB2 expression and RNF43 mutations. Other frequent mutations in both Brenner tumor-associated and teratoma-associated mucinous tumors were TP53 and KRAS mutations. Based on identical mutations or copy number profiles clonal relationships were indicated in two mucinous tumors and their associated Brenner tumor. Teratomas and Brenner tumors give rise to different subtypes of mucinous ovarian tumors. Subsequent progression pathways are comparable since both Brenner tumor-associated and teratoma-associated mucinous tumors develop a gastrointestinal immunophenotype during progression and show early mutations in KRAS and TP53. Teratoma-associated mucinous tumors may more closely resemble true gastrointestinal tumors, indicated by their expression of SATB2 and the presence of RNF43 mutations.

Clinicopathologic and Molecular Features of Paired Cases of Metachronous Ovarian Serous Borderline Tumor and Subsequent Serous Carcinoma.

Although risk factors have been established for the development of serous carcinoma after a diagnosis of serous borderline tumor (SBT), comprising atypical proliferative serous tumor (APST) (ie, conventional SBT) and noninvasive low-grade serous carcinoma (niLGSC) (ie, micropapillary SBT), subsequent invasive carcinoma still occurs in a subset of women who are not at increased risk. Whether subsequent serous carcinoma in women with a prior SBT represents malignant progression/recurrence or an independent primary tumor is unclear, and the combined clinicopathologic and molecular features of SBTs and their subsequent carcinomas have not been fully characterized. In this study, we analyzed a cohort of 42 women initially diagnosed with SBT who subsequently developed serous carcinoma of a total of 1025 cases of ovarian SBT from a nationwide population-based cohort. Review of the diagnostic slides was performed from this subset of SBTs and matched metachronous invasive serous carcinomas (39 low grade, 3 high grade). DNA was extracted from tissue blocks available for 41 cases (both SBT and carcinoma, n=36; SBT only, n=3; carcinoma only, n=2). Samples were subjected to digital droplet PCR to analyze mutation hotspots in KRAS (codon 12) and BRAF (V600E), which are frequently found in low-grade serous tumors. Eighty-one percent of SBTs (34/42) were APST, and 19% (8/42) were niLGSC. Forty percent of cases (17/42) were FIGO stage I, the majority of which were APST (14/17; 82%). The median time to development of carcinoma was 9 years (range, 0.6 to 25 y). Mutations in SBTs were distributed as follows: 5/39 (13%) BRAF mutant, 22/39 (56%) KRAS mutant, and 12/39 (31%) wild-type for both genes. There was a significant relationship between SBT gene mutation and histologic type, with BRAF mutations occurring exclusively in APST and a higher frequency of niLGSC among SBTs wild-type for BRAF and KRAS (P=0.01). The diffuse presence of tumor cells with abundant eosinophilic cytoplasm was significantly associated with the BRAF mutation (P=0.001). Mutational analyses of matched SBT/carcinoma pairs revealed concordant profiles in 33/36 (92%) cases, of which 19 (53%) were KRAS mutant, 4 (11%) were BRAF mutant, and 10 (28%) were wild type for both genes. The 3 discordant cases consisted of a wild-type niLGSC with a subsequent BRAF-mutant invasive LGSC, a KRAS-mutant APST with a KRAS-mutant LGSC, and a BRAF-mutant APST with subsequent development of a KRAS-mutant high-grade serous carcinoma. In conclusion, some women with SBTs can subsequently develop serous carcinoma, occasionally over 10 years later. Most subsequent carcinomas are low grade, but a small subset can be high grade. The type of gene mutation in SBT correlates with various histologic features. While most cases of serous carcinoma developing after a diagnosis of SBT probably represent tumor progression, a minority are independent primary tumors, presumably arising from endosalpingiosis.

Nine-valent HPV vaccine efficacy against related diseases and definitive therapy: comparison with historic placebo population.

OBJECTIVE: Nine-valent human papillomavirus (9vHPV) vaccine efficacy against disease and cervical surgeries related to all nine vaccine components was assessed compared with a historic placebo population. This was not assessed in the 9vHPV vaccine efficacy trial since the trial was quadrivalent HPV (qHPV) vaccine-controlled, efficacy was measured for the five HPV types covered only by 9vHPV vaccine (HPV31/33/45/52/58), but not the four types covered by both vaccines (HPV6/11/16/18). METHODS: Three international, randomized, double-blind studies were conducted using the same methodology. In the 9vHPV vaccine study (NCT00543543), 7106 and 7109 women received 9vHPV or qHPV vaccine, respectively. In the historic qHPV vaccine studies (FUTURE I [NCT00092521] and II [NCT00092534]), 8810 and 8812 women received qHPV vaccine or placebo, respectively, based on the same eligibility criteria. Cervical cytological testing was performed regularly. Biopsy or definitive therapy specimens were assessed for HPV DNA. RESULTS: Among women negative for 14 HPV types prior to vaccination, incidence of high-grade cervical disease (9vHPV, n = 2 cases; placebo, n = 141 cases) and cervical surgery (9vHPV, n = 3 cases; placebo, n = 170 cases) related to the nine HPV types was reduced by 98.2% (95% confidence interval [CI], 93.6-99.7) and 97.8% (95% CI, 93.4-99.4), respectively. The 9vHPV vaccine did not prevent disease related to vaccine HPV types detected at baseline, but significantly reduced cervical, vulvar, and vaginal diseases related to other vaccine HPV types. CONCLUSIONS: Effective implementation of the 9vHPV vaccine may substantially reduce the burden of HPV-related diseases and related medical procedures. TRIAL REGISTRATIONS: clinicaltrials.gov: NCT00543543, NCT00092521, NCT00092534.

Comprehensive Surgical Staging in Stage 1 Clear Cell and Endometrioid Ovarian Carcinomas: Is it Necessary?

The objective of this article was to evaluate the presence of occult metastasis after comprehensive surgical staging of clear cell ovarian carcinoma (CCC) and endometrioid ovarian carcinoma (EMCA) that appeared to be confined to the ovary at time of surgery. Between 1998 to 2016, 85 patients with CCC and EMCA were identified who were comprehensively staged and felt to be stage 1 intraoperatively. Of the 85 patients who underwent surgical staging, 4 (4.7%) had omental and dense pelvic side-wall tumor adhesions. On final pathology, 67 (79%) patients were diagnosed as stage 1A of which 29 (43%) patients were upstaged to 1C1 due to intraoperative rupture. The remaining 18 (21%) patients were staged as 1C2/1C3. The 1- and 5-yr disease-free survival for pathology stage 1A tumors was 94% and 76%, respectively, and for 1C2/1C3 tumors was 100% and 75%, respectively. Among patients who received adjuvant chemotherapy, the 5-yr disease-free survival was near equal for pathology stage 1A and 1C2/1C3 groups (73% vs. 74%), with a lower 5-yr disease-free survival for CCC compared with EMCA (72% vs. 78%). There were 16 (19%) recurrences with 12 being pathology stage 1A. Of these 12 patients, 9 (75%) had CCC of which 2 received adjuvant chemotherapy. Even in the presence of dense adhesions (4.7%), the likelihood of extraovarian disease in CCC and EMCA confined to the ovary was very low. Accordingly, the findings in this study indicate that comprehensive surgical staging for what appears to be stage 1 CCC and EMCA may provide no benefit in detecting occult disease that would upstage the tumor.

Genomic landscape and evolutionary trajectories of ovarian cancer precursor lesions.

The clonal relationship between ovarian high-grade serous carcinoma (HGSC) and its presumed precursor lesion, serous tubal intraepithelial carcinoma (STIC), has been reported. However, when analyzing patients with concurrent ovarian carcinoma and tubal lesion, the extensive carcinoma tissues present at diagnosis may have effaced the natural habitat of precursor clone(s), obscuring tumor clonal evolutionary history, or may have disseminated to anatomically adjacent fimbriae ends, masquerading as precursor lesions. To circumvent these limitations, we analyzed the genomic landscape of incidental tubal precursor lesions including p53 signature, dormant STIC or serous tubal intraepithelial lesion (STIL) and proliferative STIC in women without ovarian carcinoma or any cancer diagnosis using whole-exome sequencing and amplicon sequencing. In three of the four cancer-free women with multiple discrete tubal lesions we observed non-identical TP53 mutations between precursor lesions from the same individual. In one of the four women with co-existing ovarian HGSC and tubal precursor lesion we found non-identical TP53 mutations and a lack of common mutations shared between her precursor lesion and carcinoma. Analyzing the evolutionary history of multiple tubal lesions in the same four patients with concurrent ovarian carcinoma indicated distinct evolution trajectories. Collectively, the results support diverse clonal origins of tubal precursor lesions at the very early stages of tumorigenesis. Mathematical modeling based on lesion-specific proliferation rates indicated that p53 signature and dormant STIC may take a prolonged time (two decades or more) to develop into STIC, whereas STIC may progress to carcinoma in a much shorter time (6 years). The above findings may have implications for future research aimed at prevention and early detection of ovarian cancer. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Human Papillomavirus Genotypes From Vaginal and Vulvar Intraepithelial Neoplasia in Females 15-26 Years of Age.

OBJECTIVE: To estimate the proportion of vulvar and vaginal low-grade and high-grade squamous intraepithelial lesions (LSILs and HSILs) in females 15-26 years of age attributable to 14 human papillomavirus (HPV) genotypes (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59). METHODS: A post hoc analysis of prospectively diagnosed vulvar and vaginal LSILs and HSILs among females 15-26 years of age enrolled in the placebo arms of two phase 3, randomized HPV vaccine trials assessed 14 prespecified HPV genotypes associated with cervical cancers or anogenital warts using a type-specific multiplex polymerase chain reaction assay. The frequency of lesions associated with specific HPV genotypes was estimated by proportional and other attribution methods. RESULTS: During approximately 4 years of follow-up in 8,798 females, 40 vulvar LSILs and 46 vulvar HSILs were diagnosed in 68 females, and 118 vaginal LSILs and 33 vaginal HSILs were diagnosed in 107 females. Females developing vulvar (41.2%) or vaginal (49.5%) lesions also had cervical lesions, whereas 6.5% of females with cervical lesions had vaginal or vulvar lesions. At least 1 of the 14 HPV genotypes was detected in females with vulvar LSIL (72.5%), vulvar HSIL (91.3%), vaginal LSIL (61.9%), and vaginal HSIL (72.7%). Considering only HPV-positive lesions, the nine most common genotypes causing cervical cancer and anogenital warts (6, 11, 16, 18, 31, 33, 45, 52, and 58) were found in 89.4% of vulvar LSILs, 100% of vulvar HSILs, 56.0% of vaginal LSILs, and 78.3% of vaginal HSILs. CONCLUSION: Most vulvar and vaginal lesions were attributable to at least 1 of the 14 HPV genotypes analyzed. Effective immunization programs could potentially prevent substantial numbers of HPV-related vulvar and vaginal LSILs and HSILs. CLINICAL TRIAL REGISTRATION: CLINICALTRIALS.GOV,: NCT00092521 and NCT00092534.

Evaluation of liquid from the Papanicolaou test and other liquid biopsies for the detection of endometrial and ovarian cancers.

We report the detection of endometrial and ovarian cancers based on genetic analyses of DNA recovered from the fluids obtained during a routine Papanicolaou (Pap) test. The new test, called PapSEEK, incorporates assays for mutations in 18 genes as well as an assay for aneuploidy. In Pap brush samples from 382 endometrial cancer patients, 81% [95% confidence interval (CI), 77 to 85%] were positive, including 78% of patients with early-stage disease. The sensitivity in 245 ovarian cancer patients was 33% (95% CI, 27 to 39%), including 34% of patients with early-stage disease. In contrast, only 1.4% of 714 women without cancer had positive Pap brush samples (specificity, ~99%). Next, we showed that intrauterine sampling with a Tao brush increased the detection of malignancy over endocervical sampling with a Pap brush: 93% of 123 (95% CI, 87 to 97%) patients with endometrial cancer and 45% of 51 (95% CI, 31 to 60%) patients with ovarian cancer were positive, whereas none of the samples from 125 women without cancer were positive (specificity, 100%). Finally, in 83 ovarian cancer patients in whom plasma was available, circulating tumor DNA was found in 43% of patients (95% CI, 33 to 55%). When plasma and Pap brush samples were both tested, the sensitivity for ovarian cancer increased to 63% (95% CI, 51 to 73%). These results demonstrate the potential of mutation-based diagnostics to detect gynecologic cancers at a stage when they are more likely to be curable.

Atypical Proliferative (Borderline) Serous Tumor in the Brain: A Case Report.

A 59-year-old woman with a remote history of invasive ductal carcinoma of the breast was found on a follow-up computed tomography scan of her brain to have a 1-cm lesion in the right frontal lobe in 2008. In the ensuing years, before her current admission, multiple imaging studies of the brain revealed that the lesion was stable and it was, therefore, interpreted as a small area of encephalomalacia related to a thrombosed cortical vein, a cavernoma, or treated metastatic breast cancer. In 2013, the patient underwent a bilateral salpingo-oophorectomy for ovarian tumors that were diagnosed as bilateral serous cystadenofibromas. A partial omentectomy showed no evidence of implants. In June 2016, the brain lesion was completely excised and diagnosed as an atypical proliferative (borderline) serous tumor. Immunohistochemical staining demonstrated that the tumor cells were immunoreactive for Pax8, WT-1, ER, and CK-7 and negative for Gata-3, PR, TTF-1, CDX-2, Napsin A, and CK-20, which was consistent with that diagnosis. We present a brief review of possible mechanisms to account for this unusual presentation and speculate that the most likely one is exfoliation of fallopian tube epithelial cells into the peritoneal cavity, which then gain access to lymphatics resulting in cells implanting in the brain and subsequently progressing to an atypical proliferative (borderline) serous tumor.

Molecular analysis of high-grade serous ovarian carcinoma with and without associated serous tubal intra-epithelial carcinoma.

Many high-grade serous carcinomas (HGSCs) of the pelvis are thought to originate in the distal portion of the fallopian tube. Serous tubal intra-epithelial carcinoma (STIC) lesions are the putative precursor to HGSC and identifiable in ~ 50% of advanced stage cases. To better understand the molecular etiology of HGSCs, we report a multi-center integrated genomic analysis of advanced stage tumors with and without STIC lesions and normal tissues. The most significant focal DNA SCNAs were shared between cases with and without STIC lesions. The RNA sequence and the miRNA data did not identify any clear separation between cases with and without STIC lesions. HGSCs had molecular profiles more similar to normal fallopian tube epithelium than ovarian surface epithelium or peritoneum. The data suggest that the molecular features of HGSCs with and without associated STIC lesions are mostly shared, indicating a common biologic origin, likely to be the distal fallopian tube among all cases.High-grade serous carcinomas (HGSCs) are associated with precursor lesions (STICs) in the fallopian epithelium in only half of the cases. Here the authors report the molecular analysis of HGSCs with and without associated STICs and show similar profiles supporting a common origin for all HGSCs.

Long-term Behavior of Serous Borderline Tumors Subdivided Into Atypical Proliferative Tumors and Noninvasive Low-grade Carcinomas: A Population-based Clinicopathologic Study of 942 Cases.

Ovarian serous borderline tumors (SBTs) have been the subject of considerable controversy, particularly with regard to terminology and behavior. It has been proposed that they constitute a heterogenous group of tumors composed, for the most part, of typical SBTs that are benign and designated "atypical proliferative serous tumor (APST)" and a small subset of SBTs with micropapillary architecture that have a poor outcome and are designated "noninvasive low-grade serous carcinoma (niLGSC)". It also has been argued that the difference in behavior between the 2 groups is not due to the subtype of the primary tumor but rather the presence of extraovarian disease, specifically invasive implants. According to the terminology of the 2014 WHO Classification, typical SBTs are equivalent to APSTs and SBTs displaying micropapillary architecture are synonymous with niLGSC. In addition, "invasive implants" were renamed "low-grade serous carcinoma" (LGSC). The argument as to whether it is the appearance of the primary tumor or the presence of extraovarian LGSC that determines outcome remains unsettled. The current study was initiated in 2004 and was designed to determine what factors were predictive of outcome, with special attention to the appearance of the primary tumor (APST vs. niLGSC) and that of the extraovarian disease (noninvasive vs. invasive implants). Our study is population based, involving the entire female population of Denmark. None of the women in the study were lost to follow-up, which ranged up to 36 years (median, 15 y). All the microscopic slides from the contributing hospitals were rereviewed by a panel of 2 pathologists (R.V. and R.J.K.) who were blinded to the follow-up. After excluding those that were not SBTs by the pathology panel, as well as cases with a prior or concurrent cancer or undefined stage, 942 women remained, of which 867 were APSTs and 75 were niLGSCs. The median patient age was 50 years (range, 16 to 97 y). Eight hundred nine women (86%) presented with FIGO stage I disease, whereas 133 (14%) had advanced stage disease. Compared with APSTs, niLGSC exhibited a significantly greater frequency of bilaterality, residual gross disease after surgery, microinvasion/microinvasive carcinoma, advanced stage disease, and invasive implants at presentation (P-values <0.003). Because the cause of death is difficult to accurately ascertain from death certificates, we used development of invasive serous carcinoma as the primary endpoint as following development of carcinoma, the mortality is very high. In the entire cohort, subsequent development of carcinoma occurred in 4%, of which 93% were low grade and 7% high grade (median time, 10 y; range, up to 25 y). After adjusting for age at and time since diagnosis of APST or niLGSC, occurrence of subsequent carcinoma was significantly higher with niLGSC than APST among all stages combined (hazard ratio [HR]=3.8; 95% confidence interval [CI], 1.7-8.2). This difference was still significant for stage I but not advanced stage cases. Moreover, all-cause mortality was not statistically significantly different between APST and niLGSC. Of all women with advanced stage disease, 114 (86%) had noninvasive implants, whereas 19 (14%) were invasive. Noninvasive implants were significantly associated with subsequent development of carcinoma (HR=7.7; 95% CI, 3.9-15.0), but the risk with invasive implants was significantly higher (HR=42.3; 95% CI, 16.1-111.1). In conclusion, although invasive implants are the most important feature in predicting an adverse outcome, subclassification into APST and niLGSC is important as it stratifies women with respect to risk for advanced stage disease and invasive implants for all women and development of serous carcinoma for stage I cases.

Parity, infertility, oral contraceptives, and hormone replacement therapy and the risk of ovarian serous borderline tumors: A nationwide case-control study.

OBJECTIVE: Few studies have examined the risk of an ovarian serous borderline tumor (SBT) associated with parity, infertility, oral contraceptives (OCs), or hormone replacement therapy (HRT), which was the study aim. METHODS: This nationwide case-control study included all women with an SBT diagnosis in Denmark, 1978-2002. SBTs were confirmed by centralized expert pathology review. For each case, 15 age-matched female controls were randomly selected using risk-set sampling. Cases and controls with previous cancer (except for non-melanoma skin cancer) and controls with bilateral oophorectomy or salpingo-oophorectomy were excluded. Conditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We found a strongly decreased risk of SBTs among parous women which decreased with increasing number of children (p<0.01). Older age at first birth also decreased the SBT risk (p=0.03). An increased SBT risk was associated with infertility (OR=3.31; 95% CI: 2.44-4.49), which was present both among parous and nulliparous women. HRT use increased the SBT risk (OR=1.32; 95% CI: 1.02-1.72), whereas OC use decreased the risk (OR=0.40; 95% CI: 0.26-0.62). CONCLUSIONS: Our nationwide study with expert histopathologic review of all SBTs showed that parity, infertility, use of HRT, and use of OCs, respectively, were strongly associated with the risk of SBTs. This is the first study to report a strong and significantly decreased SBT risk associated with OC use and a significantly increased risk with infertility, and HRT use. This supports that SBTs and serous ovarian cancer share similar risk factors.

Steroid hormone synthesis by the ovarian stroma surrounding epithelial ovarian tumors: a potential mechanism in ovarian tumorigenesis.

Epithelial ovarian tumors are responsive to steroid hormone stimulation and the ovarian stroma may have a direct role in this process. We evaluated immunohistochemical markers of sex-steroid differentiation and steroidogenesis (calretinin, inhibin, steroidogenic factor 1), steroid enzymes involved in hormone biosynthesis (CYP17, CYP19, HSD17ß1, AKR1C3), and hormone receptors (estrogen receptor, progesterone receptor, and androgen receptor) in 101 epithelial ovarian tumors and in normal structures implicated in ovarian carcinogenesis (ovarian surface epithelium and cortical inclusion cysts) in an attempt to elucidate this process. We hypothesized that ovarian stroma immediately adjacent to tumors express markers of sex-steroid differentiation and steroidogenesis and steroid enzymes whereas the epithelium contains corresponding hormone receptors. As the findings in seromucinous, endometrioid, and clear cell neoplasms, tumors closely associated with endometriosis, were very similar, these were combined into a group designated 'endometriosis-related tumors.' Significantly increased expression of markers of sex-steroid differentiation and steroidogenesis was found in stroma immediately adjacent to endometriosis-related tumors (P=0.003) and mucinous tumors (primary and metastatic mucinous tumors were combined because of similar findings) (P<0.0001) compared with more remote ovarian stroma. In addition, sex-steroid enzymes were increased in stroma adjacent to endometriosis-related tumors (P=0.02) and mucinous tumors (P=0.02) compared with more distant stroma. Steroid hormone receptors showed greater expression in epithelium compared with stroma in the endometriosis-related tumors (P=0.0009), low-grade serous tumors (P<0.0001), and high-grade serous carcinoma (P=0.0036). In contrast, there was greater expression in stroma compared with epithelium (P<0.0001) in mucinous tumors, which may be due to the fact that they are not derived from müllerian epithelium. In conclusion, our findings strongly support the view that the stroma surrounding epithelial tumors in the ovary is activated to elaborate steroid hormones which may stimulate further neoplastic growth. The precise mechanisms by which this process might occur are complex and require further investigation.

PD-L1 Expression in Human Placentas and Gestational Trophoblastic Diseases.

One of the major immune checkpoints responsible for immune evasion in cancer cells is the interaction between programmed cell death-1 (PD-1) and its ligand (PD-L1). As human trophoblastic cells display many of the features of malignant cells such as the ability to invade normal tissue including blood vessels and are apparently not eradicated by the host immune system, we undertook the present study to determine whether PD-L1 was upregulated in different types of trophoblastic cells during normal pregnancy and in gestational trophoblastic diseases. Immunohistochemistry using an anti-PD-L1-specific antibody demonstrated that in early and term normal placentas, PD-L1 was highly expressed in syncytiotrophoblast and to a much lower extent in intermediate trophoblastic cells located in the chorion laeve and implantation site. PD-L1 immunoreactivity was undetectable in cytotrophoblastic cells. This staining pattern in normal placenta was recapitulated in various types of gestational trophoblastic disease. PD-L1 was highly expressed by syncytiotrophoblast in complete moles and choriocarcinomas. The intermediate trophoblastic neoplasms, placental site trophoblastic tumors, and epithelioid trophoblastic tumors showed variable PD-L1 immunoreactivity but at a lower intensity than in the neoplastic syncytiotrophoblast in choriocarcinoma. In addition, we observed PD-1-positive lymphocytes located within the implantation site and in trophoblastic tumors. In summary, this study describes a novel mechanism for trophoblastic cells to create a tolerogenic feto-maternal interface by upregulating PD-L1 in syncytiotrophoblast and in intermediate trophoblast. Trophoblastic tumors may also use PD-L1 expression to evade the host immune response thereby promoting their survival.

A nationwide study of ovarian serous borderline tumors in Denmark 1978-2002. Risk of recurrence, and development of ovarian serous carcinoma.

OBJECTIVE: Absolute risk and risk factors for recurrence and ovarian serous carcinoma following ovarian serous borderline tumors (SBTs) is not well-established. METHODS: We included all women with SBTs in Denmark, 1978-2002. Diagnoses were confirmed by centralized pathology review and classified as atypical proliferative serous tumor (APST) or noninvasive low-grade serous carcinoma (LGSC). Implants were classified as noninvasive or invasive. Medical records were collected and reviewed, and follow-up was obtained. Subsequent diagnoses were also confirmed by centralized pathology review. We examined absolute risk and risk factors for recurrent APST and serous carcinoma using Cox regression. RESULTS: The absolute serous carcinoma risk after, respectively, 5 and 20years was 5.0% and 13.9% for noninvasive LGSC, and 0.9% and 3.7% for APST. Serous carcinoma risk was significantly higher following noninvasive LGSC compared with APST among stage I patients/patients without implants (HR=5.3; 95% CI: 1.7-16.3), whereas no significant association with tumor type was found in advanced stage patients/patients with implants. Advanced stage - notably invasive implants - bilaterality, surface involvement, and residual disease increased serous carcinoma risk. However, women with stage I APST also had a higher risk than the general population. CONCLUSIONS: This largest population-based cohort of verified SBTs revealed that women with noninvasive LGSC are significantly more likely to develop serous carcinoma than women with APST, which could not entirely be explained by invasive implants. Although invasive implants was a strong risk factor for serous carcinoma, even women with stage I APST were at increased risk compared with the general population.

Diagnostic potential of tumor DNA from ovarian cyst fluid.

We determined whether the mutations found in ovarian cancers could be identified in the patients' ovarian cyst fluids. Tumor-specific mutations were detectable in the cyst fluids of 19 of 23 (83%) borderline tumors, 10 of 13 (77%) type I cancers, and 18 of 18 (100%) type II cancers. In contrast, no mutations were found in the cyst fluids of 18 patients with benign tumors or non-neoplastic cysts. Though large, prospective studies are needed to demonstrate the safety and clinical utility of this approach, our results suggest that the genetic evaluation of cyst fluids might be able to inform the management of the large number of women with these lesions.

CCNE1 amplification and centrosome number abnormality in serous tubal intraepithelial carcinoma: further evidence supporting its role as a precursor of ovarian high-grade serous carcinoma.

Aberration in chromosomal structure characterizes almost all cancers and has profound biological significance in tumor development. It can be facilitated by various mechanisms including overexpression of cyclin E1 and centrosome amplification. As ovarian high-grade serous carcinoma has pronounced chromosomal instability, in this study we sought to determine whether increased copy number of CCNE1 which encodes cyclin E1 and centrosome amplification (>2 copies) occurs in its putative precursor, serous tubal intraepithelial carcinoma. We found CCNE1 copy number gain/amplification in 8 (22%) of 37 serous tubal intraepithelial carcinomas and 12 (28%) of 43 high-grade serous carcinomas. There was a correlation in CCNE1 copy number between serous tubal intraepithelial carcinoma and high-grade serous carcinoma in the same patients (P<0.001). There was no significant difference in the percentage of CCNE1 gain/amplification between serous tubal intraepithelial carcinoma and high-grade serous carcinoma (P=0.61). Centrosome amplification was recorded in only 5 (14%) of 37 serous tubal intraepithelial carcinomas, and in 10 (40%) of 25 high-grade serous carcinomas. The percentage of cells with centrosome amplification was higher in high-grade serous carcinoma than in serous tubal intraepithelial carcinoma (P<0.001). Induced expression of cyclin E1 increased the percentage of fallopian tube epithelial cells showing centrosome amplification. Our findings suggest that gain/amplification of CCNE1 copy number occurs early in tumor progression and precedes centrosome amplification. The more prevalent centrosome amplification in high-grade serous carcinoma than in serous tubal intraepithelial carcinoma supports the view that serous tubal intraepithelial carcinoma precedes the development of many high-grade serous carcinomas.

The Dualistic Model of Ovarian Carcinogenesis: Revisited, Revised, and Expanded.

Since our proposal of a dualistic model of epithelial ovarian carcinogenesis more than a decade ago, a large number of molecular and histopathologic studies were published that have provided important insights into the origin and molecular pathogenesis of this disease. This has required that the original model be revised and expanded to incorporate these findings. The new model divides type I tumors into three groups: i) endometriosis-related tumors that include endometrioid, clear cell, and seromucinous carcinomas; ii) low-grade serous carcinomas; and iii) mucinous carcinomas and malignant Brenner tumors. As in the previous model, type II tumors are composed, for the most part, of high-grade serous carcinomas that can be further subdivided into morphologic and molecular subtypes. Type I tumors develop from benign extraovarian lesions that implant on the ovary and which can subsequently undergo malignant transformation, whereas many type II carcinomas develop from intraepithelial carcinomas in the fallopian tube and, as a result, disseminate as carcinomas that involve the ovary and extraovarian sites, which probably accounts for their clinically aggressive behavior. The new molecular genetic data, especially those derived from next-generation sequencing, further underline the heterogeneity of ovarian cancer and identify actionable mutations. The dualistic model highlights these differences between type I and type II tumors which, it can be argued, describe entirely different groups of diseases.